β-Ala Containing Peptides: Potentials in Design and Construction of Bioactive Peptides and Protein Secondary Structure Mimics

Raghuvansh      Kishore

doi:10.2174/1389203043379396

Abstract

In recent years, there has been increasing interest in de novo design and construction of novel synthetic peptides that mimic protein secondary structures, i.e., turns, helices and sheets. The unique structural influences exerted by unsubstituted, non-coded, non-chiral βamino acid, i.e., βalanine (βAla; 3- or beta- aminopropionic acid) on peptide backbone, when inserted into peptide chain comprised α-amino acids, offer an excellent opportunity to design and construct diverse well-defined three-dimensional structures. Our current understanding of folding-unfolding behavior of the βAla residues relies primarily from an examination of conformational preferences of a large number of short cyclicas well as acyclic βAla containing peptides investigated using single crystal X-ray diffraction analysis. In addition, theoretical conformational energy calculations and different spectroscopic techniques: 1H NMR, FT-IR and CD, have also been employed although, to a lesser extent. The obtainable results tend to reveal overwhelming preferences of the βAla moiety for the folded gauche (m ∼ ± 65±10 ) conformation in cyclic- and for an extended trans (m ∼ ±165±10 ) as well as gauche (m ∼ ±65±10 ) orientations in acyclic βAla containing peptides. The results also indicate that in short linear βAla containing peptides, the specific influence of selective neighboring side-chain substituents e.g. linear- or cyclic symmetrically Ca,a-disubstituted glycines and other conformational constraints, may be significant in controlling the overall folded-unfolded topographical features across the two methylene units (-CbH2-CaH2-) of the βAla residue. Taking into consideration the wide occurrence of βAla moiety in animal and plant kingdoms and the remarkable structural versatility of the peptides incorporating βAla residue(s), together with appreciable resistance towards enzymatic degradation, hold strong promise for biophysicists and biochemists not only to design molecules that fold to mimic protein secondary structures but also to develop potent peptide analo gs and peptidomimetics displaying unique pharmaceutical properties.

Keywords: secondary structure mimics, bioactive peptides, solid- and solution state molecular conformations, spectroscopic and X-ray diffraction studies

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